Quinazoline derivatives

ABSTRACT

The present invention provides a new compound which shows slow and continuous blood pressure reducing action and is useful as an antihypertensive agent. 
     The invention resides in a quinazoline derivative of the following formula (I) and its pharmaceutically acceptable salt:                    
     in which, each of R 1  and R 2  is H or an alkyl group of 1 to 6 carbon atoms, or R 1  and R 2  are combined to form an ethylene group; each of R 3  and R 4  is an alkyl group of 1 to 6 carbon atoms; R 5  is a hydrogen atom, a hydroxyl group, an alkyl group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms; each of R 6  and R 7  is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; and n is 2 or 3. The invention further resides in an antihypertensive agent containing the above compound.

FIELD OF THE INVENTION

This invention relates to quinazoline derivatives showing slow andcontinuous blood pressure reducing action and an antihypertensive agentcontaining the same.

BACKGROUND OF THE INVENTION

An example of a quinazoline type compound employed for a knownantihypertensive agent is the following compound [A] which is describedin U.S. Pat. No. 3,511,836 and is commercially available as “Prazosinhydrochloride”:

Also known is the following compound [B] of the quinazoline typeantihypertensive agent which is also commercially available as“Terazosin hydrochloride”:

The known antihypertensive agents of the quinazoline type such as the“Prazosin hydrochloride” and “Terazosin hydrochloride” are short intheir half-life in blood and show their blood pressure reducing actionrapidly. Therefore, these known antihypertensive agents frequently showside-effects named “first dose phenomenon”, such as orthostatichypotension, palpitation, and tachycardia, immediately after theiradministration. For the reason, they have not been generally employedfor treatment of hypertension at the initial stage. Recently, doxazosinmesilate which belongs to the quinazoline derivative and which showslong half-life in blood and slow blood pressure reducing action ascompared with the prazosin hydrochloride has been developed. Thedoxazosin mesilate is reported to control blood pressure for a long timesuch as 24 hours by its administration once a day and seldom gives sideeffects such as orthostatic hypotension (J. Clin. Pharm. Ther., 14:283(1989)).

Also known is an antihypertensive agent of a dihydropyridine typecalcium antagonist. In Medical Journal (in Japanese language), vol. 30,No. 1, 101-106 (1994), this antihypertensive agent is reported to showside effects such as blush and headache after administration. These sideeffects arise from rapidly occurring vasolidative accessory symptoms.Therefore, the Journal indicates usefulness of Amulodipine which showsslow and continuous blood pressure reducing action. The use of theantihypertensive agent showing slow and continuous blood pressurereducing action enables administration of once a day and is effective toobviate side effects such as orthostatic hypotension and vasodilativeaccessory symptoms which occurs immediately after administration.

German Patent 2,457,911 describes a quinazoline derivative of thefollowing formula [C]:

In the above patent, there is a description to the effect that thequinazoline derivative described therein shows a blood pressure reducingaction, but no pharmacological data are given.

Japanese Patent Provisional Publication 59-172478 describes aquinazoline derivative of the following formula [D]:

The quinazoline derivative described in the above ProvisionalPublication is an intermediate compound obtained in reactions and nopharmacological data are given.

Under the circumstances described above, it is considered that a newquinazoline derivative showing slow and continuous blood pressurereducing action is favorably employable as an antihypertensive agenthaving reduced side effects such as vasodilative accessory symptoms suchas blush and headache and orthostatic hypotension.

The present invention has an object to provide a new quinazolinederivative which shows slow and continuous blood pressure reducingaction.

SUMMARY OF THE INVENTION

The present invention provides a quinazoline derivative having thefollowing formula [I] and its pharmaceutically acceptable salt:

In the above formula [I], each of R¹ and R² independently represents ahydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R¹ and R²are combined to form an ethylene group (—(CH₂)₂—); each of R³ and R⁴independently represents an alkyl group having 1 to 6 carbon atoms; R⁵represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms; each ofR⁶ and R⁷ independently represents a hydrogen atom or an alkyl grouphaving 1 to 6 carbon atoms; and n is 2 or 3.

PREFERRED EMBODIMENTS OF THE INVENTION

The quinazoline derivative of the invention is described below in moredetail.

In the aforementioned formula (I), R¹ and R² can be the same ordifferent from each other and represent a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, or t-butyl. Alternatively, R¹ and R² canbe combined to form an ethylene group. The ethylene group is preferablyformed. R³ and R⁴ represents an alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ort-butyl. R³ and R⁴ can be the same alkyl or an alkyl differing from eachother. R⁵ represents a hydrogen atom, a hydroxyl group, an alkyl grouphaving 1 to 6 carbon atoms such as methyl, ethyl, n-propyl or isopropyl,or an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy,n-propoxy or isopropoxy. The hydroxyl group is preferred. R⁶ and R⁷ canbe the same or different from each other, and represents a hydrogenatom, or an alkyl group having 1 to 6 carbon atoms such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, or t-butyl. Methyl ispreferred. n is 2 or 3, and 2 is preferred.

The pharmaceutically acceptable salt of the quinazoline derivative ofthe formula [I] according to the present invention can be an inorganicacid salt such as hydrochloride, sulfate, or nitrate, or an organic acidsalt such as fumarate, mesylate, tosylate, oxalate, or citrate.

The quinazoline derivative of the invention can be synthesized by thefollowing synthetic reaction process in the same manner as described inJ. Med. Chem., 1986, 29, 19-25:

in which X represents a halogen such as chlorine or bromine, and R¹, R²,R³, R⁴, R⁵, R6,R⁷ and n have the same meanings as above.

The above-illustrated reaction can be performed by reacting2-halo-4-amino-6,7-dimethoxyquinazoline (1) and the compound (2) in aninert solvent such as an aromatic hydrocarbon (e.g., benzene, toluene,or xylene), an ether (e.g., ethyl ether, tetrahydrofuran, or dioxane),an alcohol (e.g., methanol, ethanol, propanol, or butanol), an aliphaticacid ester (e.g., methyl acetate, or ethyl acetate), an aliphaticdimethyl amide (e.g., dimethyl-formamide or dimethylacetamide), ordimethyl sulfoxide. The reaction temperature is in the range of 40 to200° C., preferably in the range of 50 to 150° C. The reaction perioddepends on the reaction temperature, and is in the range of 1 to 24hours.

Alternatively, the quinazoline derivative of the formula [I] accordingto the invention can be synthesized in the following route:

in which Y represents a halogen such as chlorine or bromine, and R¹, R²,R³, R⁴, R⁵, R⁶, R⁷ and n have the same meanings as above.

The above-illustrated reaction can be performed by reacting the compound(3) and the compound (4) in an inert solvent such as an aromatichydrocarbon (e.g., benzene, toluene, or xylene), an ether (e.g., ethylether, tetrahydrofuran, or dioxane), an alcohol (e.g., methanol,ethanol, propanol, or butanol), an aliphatic acid ester (e.g., methylacetate, or ethyl acetate), an aliphatic dimethyl amide (e.g.,dimethylformamide or dimethylacetamide), or dimethyl sulfoxide. Thereaction temperature is in the range of −10 to 200° C., preferably inthe range of −10 to 150° C. The reaction period depends on the reactiontemperature, and is in the range of 1 to 40 hours. If Y is a hydroxylgroup, the reaction can be performed in the presence of a condensatingagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodimide.

If each of R⁶ and R⁷ is a hydroxyl group, the compounds (1) and (3) canbe reacted after protecting the hydroxyl groups using a protective groupsuch as benzyl, which is removed after completion of the reaction.

Representative compounds of the aforementioned formula [I] according tothe invention are described below:

(1)N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)-amino]ethyl]-3,5-dimethylbenzenecarboxamide

(2)N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)-amino]propyl]-3,5-dimethylbenzenecarboxamide

(3)N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)-methylamino]ethyl]-3,5-dimethylbenzenecarboxamide

(4)N-methyl-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)amino]propyl]-3,5-dimethylbenzenecarboxamide

(5)N-methyl-N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]ethyl]-3,5-dimethyl-4-hydroxy-benzenecarboxamide

(6)N-methyl-N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]ethyl]-3,4,5-trimethylbenzene-carboxamide

(7)N-methyl-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(ethyl)amino]propyl]-3,5-diethyl-4-methoxy-benzenecarboxamide

(8)N-ethyl-N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(ethyl)amino]ethyl]-3,5-di-n-propyl-4-hydroxybenzenecarboxamide

(9)N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(n-propyl)amino]propyl]-3,5-diethylbenzenecarboxamide

(10)N-n-butyl-N-[2-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]ethyl]-3,5-diethyl-4-hydroxy-benzenecarboxamide

(11)N-methyl-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(t-butyl)amino]propyl]-3,5-di-t-butyl-4-hydroxybenzenecarboxamide

(12)N-isobutyl-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(ethyl)amino]propyl]-3,5-diisopropyl-4-ethoxybenzenecarboxamide

(13)N-n-propyl-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(n-propyl)amino]propyl]-3,5-dimethyl-4-hydroxybenzenecarboxamide

(14)4-amino-2-[4-(3,5-dimethylbenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(15)4-amino-2-[4-(3,5-dimethyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(16)4-amino-2-[4-(3,5-diethyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(17)4-amino-2-[4-(3,5-diethyl-4-methoxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(18)4-amino-2-[4-(3,5-diisopropyl-4-methylbenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(19)4-amino-2-[4-(3,5-diisopropyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(20)4-amino-2-[4-(3,5-di-n-butyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(21)4-amino-2-[4-(3,5-di-n-butyl-4-ethoxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(22)4-amino-2-[4-(3,5-di-t-butylbenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(23)4-amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

(24)4-amino-2-[4-(3,5-dimethyl-4-hydroxybenzoyl)-1-homopiperazinyl]-6,7-dimethoxyquinazoline

(25)4-amino-2-[4-(3,5-dimethyl-4-methoxybenzoyl)-1-homopiperazinyl]-6,7-dimethoxyquinazoline

(26)4-amino-2-[4-(3,5-di-n-propyl-4-hydroxybenzoyl)-1-homopiperazinyl]-6,7-dimethoxyquinazoline

(27)4-amino-2-[4-(3,5-di-n-propyl-4-ethylbenzoyl)-1-homopiperazinyl]-6,7-dimethoxyquinazoline

(28)4-amino-2-[4-(3,5-di-t-butylbenzoyl)-1-homo-piperazinyl]-6,7-dimethoxyquinazoline

(29) 4-amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-homopiperazinyl]-6,7-dimethoxyquinazoline

(30)4-amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-piperazinyl]-6-hydroxy-7-methoxyquinazoline

(31)4-amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-piperazinyl]-7-hydroxy-6-methoxyquinazoline

The quinazoline derivative of the formula [I] according to the inventioncan be administered through either oral or parenteral route. The oraladministration is preferred. The quinazoline derivative of the inventioncan be formulated in the form of tablets, granules, capsules, liquid, orinjections by means of conventional methods and administered in theseforms. The tablets are preferred.

The dosage of the quinazoline derivative of the formula [I] according tothe invention is in the range of 0.1 mg to 1 g/day for adult. Thequinazoline derivative of such dosage is preferably administered once ortwice a day.

Pharmacological tests for the quinazoline derivative of the formula [I]according to the invention and comparison compounds are described below.

Pharmacological Test-1

This test was performed using male spontaneously hypertensive rats (SHR,15 weeks old or older, 300 to 400 g). Under halothane anesthesia, theleft femoral arteries of the rats were cannulated using a polyethylenecannula. The cannula was connected to a device for blood pressuremeasurement. Then, the rats were placed in the Bollman-type cages. Afterone hour, it was confirmed that the blood pressure was kept constant.When the rats waked, they were orally administered with the testcompound, and variation of blood pressure after the administration wasmeasured as time passed. The test compound was suspended or dissolved in1% aqueous methylcellulose solution and administered in an amount of 0.2mL per 100 g of body weight. The test results are set forth in Table 1.

TABLE 1 Com- Dosage Number Blood Pressure (mmHg) pound (mg/kg) of rats 1hr. 3 hrs. 6 hrs. 9 hrs. 12 hrs. Con. 0 2 −2 6 −4 — — Prazo. 1 2 −35 −41−42 −41 −38 3 2 −57 −69 −65 −61 −60 Doxa. 1 1 −19 −21 −19 — — 3 1 −35−32 −29 — — 10 1 −37 −50 −35 — — Comp. 1 2 −36 −31 −39 — — [C] 3 2 −64−64 −61 — — Comp. 1 2 2 −3 −6 — — [D] 3 2 −5 −6 −8 — — Invent- 1 2 −4−25 −41 −44 −39 ion 3 2 −29 −60 −75 −64 −60 Remarks: Con.: controlPrazo.: prazosin hydrochloride Doxa.: doxazosin mesilate Comp. [C]:4-amino-2-(4-benzoyl-1-piperazinyl)-6,7-dimethoxyquinazolinehydrochloride Comp. [D]:4-amino-2-[4-(4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride Invention:4-amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride [corresponding to the aforementioned compound (23)]

As is apparent from Table 1,prazosin hydrochloride and the compound [c]give the approximately maximum blood pressure depression after a lapseof one hour, while the compound of the invention slowly decreases theblood pressure and gives the blood pressure depression at the same levelafter a lapse of six hours. The slow blood pressure depression by thecompound of the invention is also prominent even in comparison withdoxazosin mesilate. It is also apparent that the compound [D] having achemical structure analogous to the compound of the invention gives verylittle blood pressure depression.

Thus, the compound of the invention shows a slow and continuous bloodpressure reducing action and, therefore, is of value as anantihypertensive agent.

Pharmacological Test-2

This test was performed by measuring the blood pressure in the samemanner as in the above pharmacological test-1 using male DOCA salthypertensive rats (DOCAR, 15 weeks old or older, 300 to 400 g,not-fasted). The test results are set forth in Table 2.The compound ofthe invention examined in this test was the same as that employed in thepharmacological test-1.

TABLE 2 Com- Dosage Number Blood Pressure (mmHg) pound (mg/kg) of rats 1hr. 3 hrs. 6 hrs. 9 hrs. 12 hrs. Con. 0 3 −1 +4 −5 0 +6 Prazo. 3 3 −81−62 −69 −50 −36 Invention 3 3 −15 −42 −62 −49 −37

Pharmacological Test-3

This test was performed in the same manner as in the abovepharmacological test-1 using male Dahl salt sensitive male rats (DahlSR,15 weeks old or older, 300 to 400 g, not-fasted). The test results areset forth in Table 3. The compound of the invention examined in thistest was the same as that employed in the pharmacological test-1.

TABLE 3 Com- Dosage Number Blood Pressure (mmHg) pound (mg/kg) of rats 1hr. 3 hrs. 6 hrs. 9 hrs. 12 hrs. Con. 0 3 +3 +4 −8 −20 −28 Prazo. 3 3−48 −41 −43 −40 −36 Invention 3 3 −11 −25 −49 −50 −52

As is apparent from the results of Tables 1 and 2, prazosinhydrochloride gives the approximately maximum blood pressure depressionafter a lapse of one to two hours, while the compound of the inventionslowly decreases the blood pressure and gives the blood pressuredepression at the same level after a lapse of six hours. Thus, thecompound of the invention shows a slow and continuous blood pressurereducing action and, therefore, is of value as an antihypertensiveagent.

Pharmacological Test-4

This test was performed by measuring the blood pressure in the samemanner as in the above pharmacological test-1 using normal male rats ofWister strain (15 weeks old or older, 300 to 400 g, not-fasted). Thetest results are set forth in Table 4.The compound of the inventionexamined in this test was the same as that employed in thepharmacological test-1.

TABLE 4 Com- Dosage Number Blood Pressure (mmHg) pound (mg/kg) of rats 1hr. 3 hrs. 6 hrs. 9 hrs. 12 hrs. Con. 0 4 0 −1 −12 −11 −15 Prazo. 1 4−27 −21 −23 −23 −24 3 2 −44 −40 −33 −33 −43 Doxa. 3 3 −24 −19 −20 −22−23 Inven- 1 4 −4 −11 −21 −22 −23 tion 3 4 −5 −9 −19 −21 −24

As is apparent from Table 4,prazosin hydrochloride and doxazosinmesilate both largely decrease normal blood pressure, while the compoundof the invention affects the normal blood pressure only slightly. Theseresults also suggest that the compound of the invention is of value asantihypertensive agent.

SYNTHESIS EXAMPLE

4-Amino-2-[4-(3,5-di-t-butyl-4-hydroxybenzoyl)-1-piperazinyl)-6,7-dimethoxyquinazolinehydrochloride

(1) Synthesis of 1-benzyl-4-(3,5-di-t-butyl-4-hydroxy-benzoyl)piperazine

Under nitrogen atmosphere, 3,5-di-t-butyl-4-hydroxy-benzoic acid (3.10g, 12.4 mmol.) and 1-benzylpiperazine (2.00 g, 11.3 mmol.) weredissolved in dichloromethane. Under chilling with ice, to this solutionwas portionwise added 1-(3-dimethylaminopropyl) -3-ethylcarbodiimidehydrochloride (2.87 g, 15.0 mmol.), and the resulting mixture wasstirred overnight at room temperature. The reaction mixture was washedsuccessively with saturated aqueous sodium hydrogen carbonate and water,and dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=20/1), to give the desired compoundas an amorphous product (5.08 g, yield: 100%).

¹H-NMR (CDCl₃)δ:

1.43 (18H, s), 2.3-2.6 (4H, m), 3.54 (2H, s),

3.5-3.7 (4H, m), 5.37 (1H, s), 7.2-7.4 (7H, m)

(2) Synthesis of 1-(3,5-di-t-butyl-4-hydroxybenzoyl)-piperazine

In tetrahydrofuan (100 mL) was dissolved the compound (5.08 g, 12.4mmol.) obtained in (1) above. To this solution was added 10%palladium/carbon (600 mg), and the resulting mixture was stirred underhydrogen atmosphere. The reaction mixture was filtered over Celite, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform/methanol=30/1),to give the desired compound as a white crystalline product (1.50 g,yield: 38%).

¹H-NMR (CDCl₃)δ:

1.44 (18H, s), 2.9-3.2 (4H, m), 3.6-4.1 (4H, m)

5.45 (1H, brs), 7.23 (2H, s)

(3) Synthesis of4-amino-2-[4-(3,5-di-t-butyl-4-hydroxy-benzoyl)-1-piperazinyl)-6,7-dimethoxyquinazolinehydro-chloride [corresponding to the aforementioned compound (23)]

In 1-butanol (30 mL) were suspended the compound obtained in (2) above(500 mg, 1.57 mmol.) and 4-amino-2-chloro-6,7-dimethoxyquinazoline (376mg, 1.57 mmol.), and the mixture was heated under reflux for 4 hours.The reaction mixture was cooled to room temperature. The precipitatedcrystalline product was collected by filtration and washed with1-butanol, to give the desired compound as a white crystalline powderproduct (594 mg, yield: 68%).

m.p.: 253-254° C.

¹H-NMR (DMSO-d₆)δ:

1.41 (18H, s), 3.6-3.8 (4H, m), 3.85 (3H, s),

3.89 (3H, s), 3.8-4.0 (4H, m), 7.23 (2H, s),

7.40 (1H, s), 7.43 (1H, s), 7.73 (1H, s),

8.66 (1H, brs), 8.88 (1H, brs), 12.12 (1H, s)

ABILITY FOR INDUSTRIAL USE

The quinazoline derivatives of the aforementioned formula [I] providedby the present invention are useful for treating hypertension anddysuria accompanying prostatomegaly. Further, the quinazolinederivatives of the invention show slow and continuous blood pressurereducing action with giving almost no effect to normal blood pressure,and are particularly useful as antihypertensive agents.

What is claimed is:
 1. A quinazoline derivative having the followingformula [I] and its pharmaceutically acceptable salt:

in which R¹ and R² are combined to form an ethylene group; each of R³and R⁴ independently represents an alkyl group having 1 to 6 carbonatoms; R⁵ represents a hydroxyl group; R⁶ and R⁷ independentlyrepresents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;and n is 2 or
 3. 2. A quinazoline derivative having the followingformula [I] and its pharmaceutically acceptable salt:

in which R¹ and R² are combined to form an ethylene group; each of R³and R⁴ are t-butyl groups; R⁵ represents a hydroxyl group; R⁶ and R⁷independently represent a hydrogen atom or an alkyl group having 1 to 6carbon atoms; and n is 2 or
 3. 3. The quinazoline derivative of theformula [I] or its pharmaceutically acceptable salt according to claim1, wherein both of R⁶ and R⁷ are methyl groups.
 4. The quinazolinederivative of the formula [I] or its pharmaceutically acceptable saltaccording to claim 1, wherein n is
 2. 5. An antihypertensive agentcomprising, as an active ingredient, the quinazoline derivative or itspharmaceutically acceptable salt according to claim 1.